Safety of ACEi and ARB in COVID‐19 management: A retrospective analysis

Abstract Background & Aims Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2)is a highly contagious virus that has infected 260 million individuals since December 2019. The severity of coronavirus disease 2019 (COVID‐19) depends upon the complex interplay between viral factors and the host's inflammatory response, which can trigger a cascadeeventually leading to multiorgan failure. There is contradictory evidence that angiotensin‐converting enzyme (ACEi) or angiotensin receptor blockers (ARBs) may affect mortality in patients with severe COVID‐19, theoretically due to interaction with the bradykinin pathway. Therefore, we aim to explore the association between ACEi and ARB use and mortality in severe SARS‐CoV2 infection.Severe acute respiratory yndrome with coronavirus (SARS‐CoV2) is a highly contagious virus that has infected 260 million individuals since December 2019. The severity of COVID‐19 depends upon the complex interplay between viral factors and the host's inflammatory response, which can trigger a cascadeeventually leading to multiorgan failure. There is contradictory evidence that angiotensin‐converting enzyme (ACEi) or angiotensin receptor blockers (ARBs) may affect mortality in patients with severe COVID‐19, theoretically due to interaction with the bradykinin pathway. Therefore, we aim to explore the association between ACEi and ARB use and mortality in severe SARS‐CoV2 infection. Materials & Methodology This multicenter retrospective observational study enrolled 2935 COVID‐19 patients admitted at six hospitals in Southern California, USA, between March 2020 and August 2021. Our primary outcome was the association of pre‐hospital use of ACEi and ARB on in‐hospital mortality in COVID‐19 patients. First, relevant deidentified patient data were extracted using an SQL program from the electronic medical record. Then, a bivariate analysis of the relationship between ACEi and ARB use and different study variables using χ 2 and t test was done. Finally, we did a backward selection Cox multivariate regression analysis using mortality as a dependent variable. Results Of the 2935 patients in the study, hypertension was present in 40.6%, and congestive heart failure in 13.8%. ACEi and ARB were used by 17.5% and 11.3% of patients, respectively, with 28.8% of patients on either medication. After adjusting for confounding variables in the multivariate analysis, the use of ACEi (HR: 1.226, 95% CI: 0.989–1.520) or ARB (HR: 0.923, 95% CI: 0.701–1.216) was not independently associated with increased mortality. Conclusion Our results are consistent with the clinical guidelines and position statements per the International Society of Hypertension, that there is no indication to stop the use of ACEi/ARB in COVID‐19 patients.


| INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a highly pathogenic and contagious virus which has infected 500 million individuals since December 2019. It is known to primarily affect the respiratory system, creating flu-like symptoms which can eventually lead to severe hypoxia and acute respiratory distress syndrome (ARDS). 1 The severity of coronavirus disease 2019  can range depending on the complex interplay between viral factors and the host's inflammatory response which can trigger a cascade eventually leading to multiorgan failure.
According to Yang et al., 2 the patients with COVID-19 with comorbidity of hypertension (HTN) had a higher death rate (10.3%) and were more critically ill (18.3%) as compared with individuals without HTN. Since the onset of COVID-19, HTN has been found to be a major risk factor in patients. 3 The incidence of HTN and COVID-19 were reported by the Chinese Center for Disease Control to be 12.8% worldwide, while other studies have reported as high as 30% and 31%. 4,5 Angiotensin-converting enzyme (ACEi) and angiotensin receptor blockers (ARB) are the most widely prescribed antihypertensives in the market. 6 There is contradictory evidence that ACEi or ARBs may either worsen or improve COVID-19 symptoms. The proposed mechanism is discussed below.
ACE2 is a glycoprotein that is expressed in the kidney, intestine, endothelium, lungs, and heart. 7 It is hypothesized to bind with the spiked glycoprotein in SARS-Cov2. Once the binding occurs, SARS-CoV2 can cause downregulation of ACE2 resulting in increased concentrations of angiotensin II causing severe lung injury. 7 ACEi reduce angiotensin II levels which increases the proportion of ACE-2; ARBs increase angiotensin II levels by blocking its coupling with AT2 reception leading to upregulation of ACE-2 in the membrane. 7 Some studies say that the availability of ACE-2 is directly correlated with the severe inflammatory response in COVID-19 7 while others claim that the free form of ACE-2 may inactivate SARS-CoV2 and subsequently prevent the virus from entering the lungs. 7 We aim to explore the association between pre-hospital use of ACEi and ARBs and mortality in patients with COVID-19. Most of the randomized trials to date have underpowered clinical endpoints and therefore cannot comment on the safety of ACEi and ARBs on adults with COVID-19. Our study is the largest multicenter retrospective study to date with a sample size of greater than 2900 patients commenting on prior ACEi or ARB usage on mortality in COVID-19.

| Bivariate analysis
In the t test bivariate analysis of continuous variables, age, platelet count, and potassium were significantly associated with ACEi/ARB use. The mean age for patients on ACEi/ARB was 68.3 years compared to 58.7 for those not on ACEi/ARB (p < .001). The mean platelet count was 319,000/ml in those on ACEi/ARB compared to 334,000/ml in those not on ACEi/ARB (p = .01). Additionally, the mean potassium level was 4.8 meq/L in those on ACEi/ARB compared to 4.6 meq/L in those not on ACEi/ARB (p < .001) ( Table 3).
The length of stay (LOS) was similar for both patients with or without ACEi/ARB use, and the average LOS was 11 days (Table 3).
Furthermore, in the subgroup analysis mortality was higher in patients on ACEi (28.7%) compared to those on ARB (24.3%) ( Table 5).
In the Kaplan−Meier bivariate survival analysis model ( Figure S1), patients on ACEi had increased mortality compared with those not taking ACEi (p = .003). However, there was no statistically significant difference in mortality between patients who received ARBs and those who did not (p = .171) ( Figure S2). Many of the patients with comorbidities were already on antihypertensive medications such as ACEi/ARBs before hospitalization. 9 As it relates to COVID-19, patients with HTN were found to be more critically ill than those without HTN. 12  the largest multicenter retrospective study to date with a sample size of more than 2900 patients. We studied the outcomes in COVID-19

T A B L E 1 Descriptive statistics of continuous variables
patients who received pre-hospital ACEi or ARBs versus those who did not, in order to show an association with in-hospital mortality between these two groups.
We found that ACEi/ARB use was not independently associated with mortality. Our results remained consistent in our subgroup analyses stratified by age and comorbidities including HTN, CAD, CHF, and CKD.
Our findings are overall similar to prior studies, which did not find any association between the use of ACEi/ARB and mortality. For example, we looked at the results of Huang et al. 12

| Conclusion
Our results are consistent with the clinical guidelines and position statements; that there is no indication to stop ACEi/ARB in COVID-19 patients. This is consistent with the International Society of Hypertension's 14 RCT meta-analysis by Gnanethiran et al. which showed no difference in all-cause mortality between subjects receiving ACEI/ARB and those receiving the placebo.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.